CN106977575A - Method for preparing FLUTICASONE PROPIONATE form 1 - Google Patents

Abstract

The present invention relates to a novel crystallization process for the preparation of fluticasone propionate as a Form 1 polymorph having a controlled particle size and suitable for micronization. The method comprises the steps of dissolving fluticasone propionate in acetone or a mixture of acetone and water and then adding the solution to water or to a mixture of water (10) and acetone (1), whereby fluticasone Propionate crystallized out of solution as a crystalline form.

Description

Process for the preparation of fluticasone propionate form 1

This application is a divisional application of a patent application with an application date of July 6, 2012, an application number of 201280034030.3, and an invention title of "Method for preparing fluticasone propionate form 1".

The present invention relates to a novel crystallization process for the preparation of fluticasone propionate as a Form 1 polymorph with a controlled particle size and suitable for micronization.

Fluticasone propionate is a corticosteroid that is a potent anti-inflammatory agent, and it is used in Form 1 in the treatment of rhinitis, eczema, psoriasis, asthma and COPD. It has the chemical name S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-thiocarboxy ester, 17-propionate and the following chemical structures

Several processes for the preparation of fluticasone propionate, especially in its stable crystalline form 1, have been described in the literature. For example, WO 00/38811 discloses the crystallization of fluticasone propionate dissolved in acetone by mixing it with water in the presence of ultrasound radiation. WO 01/32125 discloses that by passing a stream of a solution of fluticasone propionate in acetone and a stream of water as an anti-solvent tangentially into a cylindrical mixing chamber with an axial outlet such that the streams pass to form a vortex While mixing intimately, the fluticasone propionate crystallizes. However, these methods are not easily scalable and use complex devices and techniques (such as the use of ultrasound).

Other simpler crystallization methods have also been proposed. For example, the so-called fluticasone propionate form 1 can be obtained by dissolving the crude product obtained eg in GB 2088877 in ethyl acetate followed by recrystallization.

Alternatively, WO 03/066653 has described a process for the preparation of fluticasone propionate as crystalline polymorph 1 by reacting fluticasone propionate in a non-solvating organic liquid solvent such as methyl acetate, ethyl acetate or a solution in pentanone is mixed with a non-solvating organic liquid antisolvent such as toluene, isooctane or hexane, thereby crystallizing fluticasone propionate as Form 1 from solution. However, it has been found that these crystallization methods do not provide control and flexibility with respect to the output particle size distribution of fluticasone propionate. Like most drugs intended for delivery to the lungs, fluticasone propionate is typically subjected to micronization prior to formulation to achieve the generation of respirable particles of appropriate size. However, it is well known from the literature that there is a link between the particle size of the incoming material and the size of the micronized product, so it is important to precisely control the particle size of the material fed to the microniser to ensure reliable and effective drug delivery. delivered to the lungs.

The present invention represents a solution to the problems mentioned above. The present invention does relate to a new crystallization process for the preparation of fluticasone propionate in form 1 which is scalable, reproducible and does not involve complex equipment. The crystallization method according to the present invention can also realize more flexible and accurate product particle size distribution control by changing the solvent composition. Finally, the crystallization process according to the invention shows a lower loss of product in the micronization chamber compared to conventional antisolvent crystallization.

The present invention therefore relates to a process for the preparation of fluticasone propionate in crystalline form 1 comprising the steps of dissolving fluticasone propionate in acetone or a mixture of acetone and water and then adding the solution to water or to In a mixture of water and acetone, fluticasone propionate crystallized from solution as Form 1.

According to the invention, the water or the water/acetone mixture to which the fluticasone propionate solution is added can also be referred to as "non-solvent" or "non-solvated mixture", respectively.

According to one embodiment, fluticasone propionate is dissolved in acetone containing 0 to 10% water, and the resulting solution is added to water containing 0 to 35% acetone. Preferably, fluticasone propionate is dissolved in acetone and the resulting solution is added to water containing 0 to 30% acetone.

According to another embodiment, the solution is prepared by dissolving fluticasone propionate in acetone or an acetone/water mixture at a concentration of 30 to 50 grams per liter of solvent. Preferably, the solution is prepared by dissolving fluticasone propionate in acetone or an acetone/water mixture at a concentration of 35 to 45 grams per liter of solvent.

According to a further embodiment, fluticasone propionate is dissolved in 1 volume of acetone or an acetone/water mixture and this solution is then added to a volume of water or a water/acetone mixture between 0.65 and 1.35. Preferably, 1 volume of fluticasone propionate solution is added to a volume of water or a water/acetone mixture between 0.8 and 1.2. More preferably, 1 volume of the acetone/fluticasone propionate solution is added to about 1 volume of water or a water/acetone mixture.

According to another embodiment, the addition is performed at a temperature between 10°C and 40°C. Preferably, the addition is performed at room temperature.

According to another embodiment, the addition is performed during a period between 10 minutes and 6 hours. Preferably, the addition is performed over a period of between 30 minutes and 2 hours. More preferably, the addition is performed over a period of about 1 hour.

According to another embodiment, the addition of the fluticasone propionate solution occurs via a pump in pulsed aliquots.

Nucleation and growth of fluticasone propionate occurs during and after the addition of the fluticasone propionate solution to the non-solvent or non-solvated mixture. After complete addition of the fluticasone propionate solution to the non-solvent or non-solvated mixture, the resulting slurry is stirred for a period between 0 and 12 hours, then filtered and dried. Preferably, the slurry is stirred for a period of between 1 hour and 10 hours. More preferably, the slurry is stirred for a period of between 4 hours and 8 hours. Still more preferably, the slurry is stirred for a period of about 1 hour.

The method according to the invention is particularly advantageous because it allows good flexibility and control over the physical properties of the fluticasone propionate obtained, in particular the size and shape of the particles obtained. This is illustrated in Figure 1, which shows the dependence of particle size on solvent composition when fluticasone propionate is crystallized using the method described in this invention. Surprisingly, it has been found that the specific reverse antisolvent crystallization method according to the present invention allows the crystallization of fluticasone propionate with different particle sizes by variation of the solvent composition and delivers fluticasone propionate particles that do not exhibit agglomeration, which is Typical features of conventional solvent-resistant crystallization, as described by eg Murnane et al. in Cryst. Growth Des. 2008, 8, 2753-2764 and shown in FIG. 2 .

In addition to affecting the effective delivery of intranasal and pulmonary drug formulations, control of fluticasone propionate physical properties is also important as these properties affect the bulk density, flow and downstream processing characteristics of the product.

Typically, the method according to the invention produces particles with a length of 5-200 μm and a width of 3-30 μm. The fluticasone propionate granules obtained by the method according to the invention thus have an optimal design, in particular for micronization and formulation with lactose as a dry powder and for use with a dry powder inhaler (such as the device described in, for example, WO 2005/002654 ) application. The particles of fluticasone propionate obtainable by the crystallization process described herein thus constitute a further object of the present invention.

A further and significant advantage of the granules obtained by the process according to the invention is that the yield of micronized fluticasone propionate is improved due to the lower product losses in the jet milling chamber compared to the micronized input obtained by conventional antisolvent methods. rate increase.

Fluticasone propionate may be prepared according to any method known in the literature, such as for example the method described in GB 2088877 . Alternatively, fluticasone propionate is also commercially available from various suppliers such as Hovione, Sterling or NewChem.

The particles of fluticasone propionate obtained from the crystallization process according to the invention can be micronized to a controlled size and formulated with lactose to form a dry powder blend.

Fluticasone propionate obtained from the process according to the invention is particularly suitable for micronization and administration by inhalation from a dry powder inhaler. Typically, it is administered as a dry powder as a mixture with lactose.

To this end, the granules of fluticasone propionate obtained by the process according to the invention were micronized by jet milling and subsequently admixed with lactose. The lactose used according to the invention may be anhydrous or in the form of a monohydrate. Preferably, alpha-lactose monohydrate is used. The blend thus obtained is then suitable for filling a dry powder inhaler.

The dosage unit is determined either by pre-filled capsules, blisters or sachets or by a system of dosing compartments using gravimetric feed. The unit according to the invention is generally arranged to administer a metered dose or "puff" comprising 50 to 500 μg of fluticasone propionate obtained according to the method of the invention. The total daily dosage will generally be in the range of 50 μg to 2 mg, which may be administered in a single dose, or more usually as divided doses throughout the day.

Fluticasone propionate obtained from the method according to the invention may be administered alone or in combination with one or more other drugs. Suitable examples of other therapeutic agents that may be used in combination with fluticasone propionate include, but are in no way limited to, _β2 agonists, preferably long-acting _β2 agonists, and M3 muscarinic antagonists, preferably long-acting M3 muscarinic antagonists .

Examples of suitable _β2 agonists include inter alia albuterol, terbutaline, bambuterol, fenoterol, salmeterol, formoterol, tobuterol and salts thereof. Preferably, the _β2 agonist is selected from salmeterol or formoterol and salts thereof. More preferably, the _β2 agonist is salmeterol xinafoate.

Examples of suitable M3 muscarinic antagonists include, inter alia, pratropium, oxitropium, tiotropium and salts thereof. Preferably, the M3 muscarinic antagonist is tiotropium bromide.

According to a preferred embodiment, fluticasone propionate as obtained by the method according to the invention is administered by inhalation as a dry powder alone or in combination with salmeterol xinafoate.

The following drawings and examples further illustrate the present invention.

Attached picture

Fig. 1/10 : Influence of % acetone in the antisolvent mixture on the volume median diameter D[v,0.5] of the reverse antisolvent method.

Fig. 2/10 : Crystals of fluticasone propionate obtained from example 1.

Fig. 3/10 : Crystals of fluticasone propionate obtained from example 2.

Figure 4/10 : PXRD pattern of the product of Example 2 (top line) and reference fluticasone propionate form 1 pattern (bottom line) for comparison.

Fig. 5/10 : Crystals of fluticasone propionate obtained from example 3.

Figure 6/10 : PXRD pattern of the product of Example 3 (top line) and reference fluticasone propionate form 1 pattern for comparison (bottom line).

7/10 : Crystals of fluticasone propionate obtained from Example 4.

Figure 8/10 : PXRD pattern of the product of Example 4 (top line) and reference fluticasone propionate form 1 pattern for comparison (bottom line).

Fig. 9/10 : Crystals of fluticasone propionate obtained from Example 5.

Figure 10/10 : PXRD pattern of the product of Example 5 (top line) and reference fluticasone propionate form 1 for comparison (bottom line).

Example

Example 1: Recrystallization of fluticasone propionate using standard antisolvent methods

1.0 g of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrost-1,4 -diene-17β-thiocarboxylate, 17-propionate] was mixed with 25 mL of acetone. The mixture was heated to 40°C and then cooled to 20°C. 25 mL of water was added to the solution at about 20°C. Crystallization of the product was observed during the addition. The slurry was filtered under vacuum and the isolated solid was dried in an oven at 50°C under 0.9 bar vacuum to afford fluticasone propionate form 1. The crystals obtained from this experiment are shown in FIG. 2 .

Example 2: Recrystallization of fluticasone propionate using the reverse antisolvent method of the present invention

7.5 g of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4 -diene-17β-thiocarboxylate, 17-propionate] was mixed with 225 mL of acetone. The mixture was heated to 40°C and then cooled to 10°C. The cooled solution was added to a separate stirred vessel containing 225 mL of water at 40 °C over 10 minutes. Crystallization of the product was observed during the addition. The mixture was cooled to 20 °C and maintained at this temperature for 12 hours. The slurry was filtered under vacuum and the isolated solid was dried in an oven at 50°C under 0.9 bar vacuum to yield 6.94 g of fluticasone propionate 30 (92.4% yield of theory).

The crystals obtained from this experiment are shown in FIG. 3 .

Powder X-ray Diffraction Data

Powder X-ray diffraction patterns were determined using Bruker-AXS Ltd. D4 powder X-ray diffractometer is equipped with automatic sample changer, θ-θ goniometer, automatic beam divergence slit and PSD Vantec-1 detector. Samples were prepared for analysis by mounting on a low background chamber silicon wafer sample mount. The obtained peaks were aligned against a silicon reference standard. The sample was rotated while being irradiated with copper K-α1 X-rays (wavelength = 1.5406 Angstroms), with the X-ray tube operated at 40 kV/35 mA. Analysis was performed with a goniometer run in continuous mode with a setting of 0.2 s count/0.018° step over a 2θ range of 2° to 55°. The characteristic diffraction angles of the two known polymorphs of fluticasone propionate (as reported in European Patent EP 0 937 100 B1 ) are shown in Table 1 as follows:

Table 1

The PXRD pattern of the product obtained from this experiment was shown to match that of Form 1 of fluticasone propionate, shown in FIG. 4 .

Example 3: Recrystallization of fluticasone propionate using the reverse antisolvent method of the present invention

10 g of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4- Diene-17β-thiocarboxylate, 17-propionate] was mixed with 200 mL of acetone. The mixture was heated to 40°C and then cooled to 10°C. The cooled solution was added to a separate stirred vessel containing 200 mL of water at 10°C over 10 minutes. Crystallization of the product was observed during the addition. The mixture was heated to 20°C and held at this temperature for 12 hours. The slurry was filtered under vacuum and the isolated solid was dried in an oven at 50° C. under 0.9 bar vacuum to yield 9.33 g of fluticasone propionate (93.3% yield of theory).

The crystals obtained from this experiment are shown in FIG. 5 .

The PXRD pattern of the product showed a match to that of Form 1 of fluticasone propionate, shown in FIG. 6 .

Example 4: Recrystallization of fluticasone propionate using the reverse antisolvent method of the present invention

9 g of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4- Diene-17β-thiocarboxylate, 17-propionate] was mixed with 270 mL of acetone. The mixture was heated to 40°C and then cooled to 10°C. The cooled solution was added to a separate stirred vessel containing 175 mL of water and 75 mL of acetone at 10 °C over 6 hours. Crystallization of the product was observed during the addition. The mixture was heated to 20 °C and maintained at this temperature for 12 hours. The slurry was filtered under vacuum and the isolated solid was dried in an oven at 50°C under 0.9 bar vacuum to yield 8.56 g of fluticasone propionate (95.1% yield of theory).

The crystals obtained from this experiment are shown in FIG. 7 .

The PXRD pattern of the product showed a match to that of Form 1 of fluticasone propionate, shown in FIG. 8 .

Example 5: Recrystallization of fluticasone propionate using the reverse antisolvent method of the present invention

9 g of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4- Diene-17β-thiocarboxylate, 17-propionate] was mixed with 162 mL of acetone and 18 mL of water. The mixture was heated to 40°C and then cooled to 10°C. The cooled solution was added to a separate stirred vessel containing 270 mL of water at 10 °C over 6 hours. Crystallization of the product was observed during the addition. The mixture was heated to 20 °C and filtered under vacuum. The isolated solid was dried in an oven at 50° C. under vacuum at 0.9 bar to yield 7.56 g of fluticasone propionate (84.0% yield of theory).

The crystals obtained from this experiment are shown in FIG. 9 .

The PXRD pattern of the product showed a match to that of Form 1 of fluticasone propionate, shown in FIG. 10 .

Example 6: Recrystallization of fluticasone propionate using the reverse antisolvent method of the present invention

0.958 Kg of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrost-1,4 -diene-17β-thiocarboxylate, 17-propionate] was mixed with 24.7 L of acetone. The mixture was heated to 35°C and then cooled to 20°C. The solution was added to a separate stirred vessel containing 24 L of water at 20°C over 2 hours. Crystallization of the product was observed during the addition. The mixture was maintained at 20°C for 1 hour with stirring. The slurry was filtered under vacuum and the isolated solid was dried in an oven at 75°C under 0.9 bar vacuum to afford 0.85 Kg of fluticasone propionate (88.3% of theory yield).

Example 7: Recrystallization of fluticasone propionate using the reverse antisolvent method of the present invention

2.50 Kg of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-25methyl-3-oxoandrosta-1, 4-diene-17β-thiocarboxylate, 17-propionate] was mixed with 62.5 L of acetone. The mixture was heated to 35°C and then cooled to 20°C. The solution was added to a separate stirred vessel containing 47 L of water and 15.5 L of acetone at 20°C over 2 hours. Crystallization of the product was observed during the addition. The mixture was kept at 20°C for 1 hour with stirring. The slurry was filtered under vacuum and the isolated solid was dried in an oven at 75°C under 0.9 bar vacuum to afford 2.26 Kg of fluticasone propionate (90.4% of theory yield).

Example 8: Recrystallization of Fluticasone Propionate Using the Inverse Antisolvent Method of the Invention

9.5 Kg of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4 -diene-17β-thiocarboxylate, 17-propionate] was mixed with 237.5 L of acetone. The mixture was heated to 35°C and then cooled to 20°C. The solution was added to a separate stirred vessel containing 237.5 L of water at 20°C over 4 hours. Crystallization of the product was observed during the addition. The mixture was maintained at 20°C for 4 hours with stirring. The slurry was filtered under vacuum and the isolated solid was dried in a stirred drier at 75° C. under 0.9 bar vacuum to afford 8.5 Kg of fluticasone propionate (89.2% yield of theory).

Example 9: Recrystallization of Fluticasone Propionate Using the Inverse Antisolvent Method of the Invention

2.50 Kg of fluticasone propionate [S-(fluoromethyl)-6α,9-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4 -diene-17β-thiocarboxylate, 17-propionate] was mixed with 56.25 L of acetone and 6.25 L of water. The mixture was heated to 35°C and then cooled to 20°C. The solution was added to a separate stirred vessel containing 40.6 L of water and 21.9 L of acetone at 20°C over 1 hour. Crystallization of the product was observed during the addition. The mixture was kept at 20°C for 1 hour with stirring. The slurry was filtered under vacuum and the isolated solid was dried in an oven at 75° C. under 0.9 bar vacuum to afford 2.15 Kg of fluticasone propionate (86.0% yield of theory).

Example 10: Particle Size Data Measured by Laser Diffraction

The following particle size determinations for crystalline and micronized fluticasone propionate were used in this experiment:

Particle size method for recrystallized FP:

Particle size distributions were measured on a Malvern Mastersizer 2000 laser diffraction system equipped with a Hydro 2000S liquid dispersion unit and flow cell. Samples were prepared by adding 15 drops of Tween 80 to crystalline fluticasone propionate in a glass 4 dram vial and mixing into a paste using a spatula until all powder was wetted and a fine homogeneous paste was achieved . The paste was then added to the Hydro 2000S with dispersant (0.1% Tween 80 in deionized water) using a spatula. When the obscuration target (20% ± 5%) was achieved, the samples were placed in the Hydro 2000S and stirred for 1 minute to allow the particles to wet out, disperse and ensure stable obscuration was achieved. The measurement was started after stirring for 1 minute.

Particle size method of micronized FP:

Particle size distributions were measured on a Sympatec HELOS laser diffraction system (with R1 optical module providing a measurement range of 0.1/0.18-35 μm) with a SUCELL dispersion module. 100 mg of micronized sample was weighed into a 4-Tram vial and 15 drops (approximately 0.5 mL) of Tween 80 were added to the powder from a 3 ml wide-tipped pipette. The mixture is then carefully stirred into a paste until all particles are wetted and a uniform fine paste is achieved. The paste was then added to the SUCELL with dispersant (0.025% Tween 80 in deionized water) using a spatula. Measurements were taken once the target optical concentration (10-15%) was reached.

The particle size data expressed as D[v,0.1], D[v,0.5] and D[v,0.9] obtained from Examples 2-9 are summarized in Table 2 below. D[v,0.1], D[v,0.5], and D[v,0.9] denote the 10th percentile volume diameter; the 50th percentile volume diameter; and the 90th percentile volume diameter, respectively. Typically the nth percentile volume diameter is defined such that n% of the particles have a volume equivalent particle diameter less than or equal to the nth percentile diameter. In the case of D[v,0.5], it coincides with the median value.

Table 2

This experiment shows that the particle size distribution differs by varying the solvent composition.

Example 11: Particle Size Data Before and After Micronization

The particles were micronized using a JetPharma MC150 (6 inch spiral jet mill) using the following conditions:

- Feed rate: 15g/min

-Grinding pressure: 3.5bar

-Venturi pressure: 5.5bar

- Micronization scale: 0.5Kg.

A micronization comparison of Examples 8 and 9 shows the effect of input particle size on micronization output, which is summarized in Table 3 below:

table 3

Example 12: Product recovery after micronization

An additional and significant advantage of the granules obtained by the process according to the invention compared to the micronized input obtained by conventional antisolvent methods (such as the process described in Example 1) is: the yield of micronized fluticasone propionate Increased due to lower product losses in the jet milling chamber. Several batches crystallized by conventional antisolvent techniques (as described in Example 1) or reverse antisolvent techniques according to the present invention (as described in Examples 2-9) were micronized and are presented below in Table 4 The summarized results show that the percentage of product collected after micronization was on average much higher for the reverse antisolvent product batches than for the conventional antisolvent batches. Furthermore, if the product has originated from the reverse antisolvent, a smaller portion of the product remains in the grinding chamber.

Table 4: Summary of product recovery after micronization of antisolvent and reverse antisolvent batches

crystallization technology % of batches left in the grinding chamber % of batches recovered Conventional Anti-Solvent Technology 10.6 53 Conventional Anti-Solvent Technology 13.9 46.5 Conventional Anti-Solvent Technology 5.5 35.6 Conventional Anti-Solvent Technology 8.5 59.2 Reverse antisolvent according to the invention 2.1 63.1 Reverse antisolvent according to the invention 2.2 78.9 Reverse antisolvent according to the invention 3.7 43.7 Reverse antisolvent according to the invention 1.0 63.1 Reverse antisolvent according to the invention 1.0 81

Claims (16)

1. a kind of method for being used to prepare the FLUTICASONE PROPIONATE as crystalline polymorph 1, it is characterised in that under it includes State step：FLUTICASONE PROPIONATE is dissolved in solvent and form solution, then the solution is added in aqueous non-solvent, So that FLUTICASONE PROPIONATE is crystallized out with the particle of crystalline form 1 from the solution；

Wherein, the solvent includes acetone and 0% to 10% water based on the solvent volume；And

Wherein, the non-solvent includes water and 0% to 25% acetone based on the non-solvent volume.

2. according to the method described in claim 1, wherein FLUTICASONE PROPIONATE is dissolved with the amount of every liter of 30 to 50 grams of solvent In the solvent.

3. according to the method described in claim 1, wherein FLUTICASONE PROPIONATE is dissolved in the solvent of the first determination volume To form solution, and then the solution is determined added to second in the non-solvent of volume；

Described first determines that volume and described second determines the ratio of volume 1:0.65 to 1:1.35 between.

4. method according to claim 2, wherein FLUTICASONE PROPIONATE is dissolved in the solvent of the first determination volume To form solution, and the solution is then added to the second non-solvent for determining volume；

First determines that volume determines that the ratio of volume is 1 with second:0.65 to 1:1.35.

5. the method according to claim 1, claim 2, claim 3 or claim 4, wherein the addition solution Occur at a temperature of about 10 DEG C to about 40 DEG C.

6. the method according to claim 1, claim 2, claim 3 or claim 4, wherein the addition solution Occurred in a period of about 10 minutes to about 6 hours.

7. method according to claim 5, wherein the addition solution was sent out in a period of about 10 minutes to about 6 hours It is raw.

8. the method according to claim 1, claim 2, claim 3 or claim 4, wherein the addition solution Occur in the form of pulse equal portions via pump.

9. the method according to claim 1, claim 2, claim 3 or claim 4, wherein the addition solution Occurred in a period of about 10 minutes to about 6 hours in the form of pulse equal portions via pump.

10. the method according to claim 1, claim 2, claim 3 or claim 4, wherein completing by described in Solution is added to after the step in non-solvent, and slurry is formed, between 0 to about 12 hour in a period of stir the slurry, The slurry is then filtered to be recovered as the FLUTICASONE PROPIONATE of crystalline form 1, and dries reclaimed FLUTICASONE PROPIONATE.

11. method according to claim 5, wherein completing the solution being added to after the step in non-solvent, slurry Material is formed, between 0 to about 12 hour in a period of stir the slurry, the slurry is then filtered to be recovered as crystalline form 1 FLUTICASONE PROPIONATE, and dry reclaimed FLUTICASONE PROPIONATE.

12. method according to claim 7, wherein completing the solution being added to after the step in non-solvent, slurry Material is formed, between 0 to about 12 hour in a period of stir the slurry, the slurry is then filtered to be recovered as crystalline form 1 FLUTICASONE PROPIONATE, and dry reclaimed FLUTICASONE PROPIONATE.

13. method according to claim 8, wherein completing the solution being added to after the step in non-solvent, slurry Material is formed, between 0 to about 12 hour in a period of stir the slurry, the slurry is then filtered to be recovered as crystalline form 1 FLUTICASONE PROPIONATE, and dry reclaimed FLUTICASONE PROPIONATE.

14. FLUTICASONE PROPIONATE form 1, wherein the FLUTICASONE PROPIONATE form 1 passes through according to claim 1, right It is required that 2, claim 3 or the method described in claim 4 are obtained,

Wherein described FLUTICASONE PROPIONATE form 1 has 5 microns to 35 microns of median particle.

15. FLUTICASONE PROPIONATE form 1, wherein the FLUTICASONE PROPIONATE form 1 passes through according to claim 1, right It is required that 2, claim 3 or the method described in claim 4 are obtained in granular form,

Wherein described particle does not show cohesion.

16. FLUTICASONE PROPIONATE form 1, wherein the FLUTICASONE PROPIONATE form 1 passes through according to claim 1, right It is required that 2, claim 3 or the method described in claim 4 are obtained in granular form,

The length of wherein described particle is between 5 to 200 microns, and width is between 3 to 30 microns.